Project description:This study was designed to identify highly recurrent genetic alterations typical of SÃ©zary syndrome (Sz), an aggressive cutaneous T-cell lymphoma/leukemia, possibly revealing pathogenetic mechanisms and novel therapeutic targets. High-resolution array-based comparative genomic hybridization was done on malignant T cells from 20 patients. Expression levels of selected biologically relevant genes residing within loci with frequent copy number alteration were measured using quantitative PCR. Combined binary ratio labeling-fluorescence in situ hybridization karyotyping was done on malignant cells from five patients. Minimal common regions with copy number alteration occurring in at least 35% of patients harbored 15 bona fide oncogenes and 3 tumor suppressor genes. Based on the function of the identified oncogenes and tumor suppressor genes, at least three molecular mechanisms are relevant in the pathogenesis of Sz. First, gain of cMYC and loss of cMYC antagonists (MXI1 and MNT) were observed in 75% and 40% to 55% of patients, respectively, which were frequently associated with deregulated gene expression. The presence of cMYC/MAX protein heterodimers in SÃ©zary cells was confirmed using a proximity ligation assay. Second, a region containing TP53 and genome maintenance genes (RPA1/HIC1) was lost in the majority of patients. Third, the interleukin 2 (IL-2) pathway was affected by gain of STAT3/STAT5 and IL-2 (receptor) genes in 75% and 30%, respectively, and loss of TCF8 and DUSP5 in at least 45% of patients. In sum, the Sz genome is characterized by gross chromosomal instability with highly recurrent gains and losses. Prominent among deregulated genes are those encoding cMYC, cMYC-regulating proteins, mediators of MYC-induced apoptosis, and IL-2 signaling pathway components. [Cancer Res 2008;68(8):2689â98] Keywords: aCGH, COBRA, FISH, PLA In this multicenter study, we aimed to obtain a detailed catalogue of numerical and structural chromosomal abnormalities in a group of 20 well-defined Sz patients using high-resolution array-based CGH in combination with combined binary ratio labeling (COBRA), fluorescence in situ hybridization (FISH), and in situ proximity ligation assays (PLA).

Project description:Data underlying Sander et al., Oncogene 2005, June 20, Comparative genomic hybridization on mouse cDNA microarrays and its application to a murine lymphoma model. Includes both array CGH and expression data. Abstract: Microarray-based formats offer a high-resolution alternative to conventional, chromosome-based comparative genomic hybridization (CGH) methods for assessing DNA copy number alteration (CNA) genome-wide in human cancer. For murine tumors, array CGH should provide even greater advantage, since murine chromosomes are more difficult to individually discern. We report here the adaptation and evaluation of a cDNA microarray-based CGH method for the routine characterization of CNAs in murine tumors, using mouse cDNA microarrays representing approximately 14,000 different genes, thereby providing an average mapping resolution of 109 kb. As a first application, we have characterized CNAs in a set of 10 primary and recurrent lymphomas derived from a Myc-induced murine lymphoma model. In primary lymphomas and more commonly in Myc-independent relapses, we identified a recurrent genomic DNA loss at chromosome 3G3-3H4, and recurrent amplifications at chromosome 3F2.1-3G3 and chromosome 15E1/E2-15F3, the boundaries of which we defined with high resolution. Further, by profiling gene expression using the same microarray platform, we identified within CNAs the relevant subset of candidate cancer genes displaying comparably altered expression, including Mcl1 (myeloid cell leukemia sequence 1), a highly expressed antiapoptotic gene residing within the chr 3 amplicon peak. CGH on mouse cDNA microarrays therefore represents a reliable method for the high-resolution characterization of CNAs in murine tumors, and a powerful approach for elucidating the molecular events in tumor development and progression in murine models. A disease state experiment design type is where the state of some disease such as infection, pathology, syndrome, etc is studied. Using regression correlation

Project description:Background: Osteosarcoma (OS) tumors and derived cell lines are characterized by complex chromosomal abnormalities. The availability of molecular genome profiling techniques such as array CGH have markedly enabled the high-resolution genome analysis of tumor genomes, as well as helped elucidate the mechanisms leading to their complexity. The identification of tumor-specific genomic profiles is currently the focus of many array CGH studies, but there have been no analyses to date documenting the genomic signatures consistent with chromosomal instability mechanisms in OS. Results: In this study we utilized high-resolution oligonucleotide array CGH to interrogate recurrent signatures of genomic imbalance in 10 OS tumors that were consistent with the breakage fusion bridge(BFB) mechanism. Comparative analysis of the tumors showed that they exhibited varying levels of genomic imbalance. The analysis also highlighted three chromosomal regions (6p21 ~ p22, 8q24 and 17p11.2 ~ p12) that were consistently involved in high level gain or amplification events. These three regions have been previously shown by us to be not only involved in high-level imbalance in OS-derived cell lines, but also to exhibit similar imbalance profiles consistent with BFB-related events. Karyotype and dual-color FISH analysis showed that repeated rearrangements of these unstable chromosomes through BFB cycles may create a heterogeneous pattern of copy number alterations. Conclusions: This genome-wide analysis is the first to utilize oligonucleotide array CGH and FISH analysis to derive possible genomic signatures of chromosomal instability in OS tumors. Perpetuation of the BFB cycle will create a heterogeneous pattern of copy number alterations by repeated rearrangement of the unstable tumor genome., thereby generating diverse phenotypes The resulting phenotypic diversity can generate tumors with a propensity for an aggressive disease course. A better understanding of the underlying mechanisms events leading to tumor development could result in the identification of prognostic markers and therapeutic targets. Experiment Overall Design: 10 OS tumor samples were used; fluor-flip was performed with normal human DNA as control

Project description:Data underlying Sander et al., Oncogene 2005, June 20, Comparative genomic hybridization on mouse cDNA microarrays and its application to a murine lymphoma model. Includes both array CGH and expression data. Abstract: Microarray-based formats offer a high-resolution alternative to conventional, chromosome-based comparative genomic hybridization (CGH) methods for assessing DNA copy number alteration (CNA) genome-wide in human cancer. For murine tumors, array CGH should provide even greater advantage, since murine chromosomes are more difficult to individually discern. We report here the adaptation and evaluation of a cDNA microarray-based CGH method for the routine characterization of CNAs in murine tumors, using mouse cDNA microarrays representing approximately 14,000 different genes, thereby providing an average mapping resolution of 109 kb. As a first application, we have characterized CNAs in a set of 10 primary and recurrent lymphomas derived from a Myc-induced murine lymphoma model. In primary lymphomas and more commonly in Myc-independent relapses, we identified a recurrent genomic DNA loss at chromosome 3G3-3H4, and recurrent amplifications at chromosome 3F2.1-3G3 and chromosome 15E1/E2-15F3, the boundaries of which we defined with high resolution. Further, by profiling gene expression using the same microarray platform, we identified within CNAs the relevant subset of candidate cancer genes displaying comparably altered expression, including Mcl1 (myeloid cell leukemia sequence 1), a highly expressed antiapoptotic gene residing within the chr 3 amplicon peak. CGH on mouse cDNA microarrays therefore represents a reliable method for the high-resolution characterization of CNAs in murine tumors, and a powerful approach for elucidating the molecular events in tumor development and progression in murine models. A disease state experiment design type is where the state of some disease such as infection, pathology, syndrome, etc is studied. Keywords: disease_state_design, arrayCGH, expression profiling

Project description:Background: Osteosarcoma (OS) tumors and derived cell lines are characterized by complex chromosomal abnormalities. The availability of molecular genome profiling techniques such as array CGH have markedly enabled the high-resolution genome analysis of tumor genomes, as well as helped elucidate the mechanisms leading to their complexity. The identification of tumor-specific genomic profiles is currently the focus of many array CGH studies, but there have been no analyses to date documenting the genomic signatures consistent with chromosomal instability mechanisms in OS. Results: In this study we utilized high-resolution oligonucleotide array CGH to interrogate recurrent signatures of genomic imbalance in 10 OS tumors that were consistent with the breakage fusion bridge(BFB) mechanism. Comparative analysis of the tumors showed that they exhibited varying levels of genomic imbalance. The analysis also highlighted three chromosomal regions (6p21 ~ p22, 8q24 and 17p11.2 ~ p12) that were consistently involved in high level gain or amplification events. These three regions have been previously shown by us to be not only involved in high-level imbalance in OS-derived cell lines, but also to exhibit similar imbalance profiles consistent with BFB-related events. Karyotype and dual-color FISH analysis showed that repeated rearrangements of these unstable chromosomes through BFB cycles may create a heterogeneous pattern of copy number alterations. Conclusions: This genome-wide analysis is the first to utilize oligonucleotide array CGH and FISH analysis to derive possible genomic signatures of chromosomal instability in OS tumors. Perpetuation of the BFB cycle will create a heterogeneous pattern of copy number alterations by repeated rearrangement of the unstable tumor genome., thereby generating diverse phenotypes The resulting phenotypic diversity can generate tumors with a propensity for an aggressive disease course. A better understanding of the underlying mechanisms events leading to tumor development could result in the identification of prognostic markers and therapeutic targets. Keywords: osteosarcoma, chromosomal instability, gene amplification, breakage-fusion-bridge cycle, oligonucleotide array comparative genomic hybridization

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Oncogenomic analysis of mycosis fungoides reveals major differences with Sézary syndrome

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